The objective of the proposed research is the design and synthesis of renin inhibitors. The approach which will be taken to develop potent and specific inhibitors of renin will be to synthesize compounds which resemble the postulated transition state of the renin-angiotensinogen reaction. The transition state analogues which will be synthesized possess a high degree of structural similarity to the postulated renin-angiotensinogen transition state in that they contain functional groups which mimic the tetrahedral nature of the Leu10 carbonyl group and the amino characteristics of the alpha-nitrogen atom of the Leu11 residue. The ability of the transition state analogues to inhibit renin will be determined. Renin activity will be assayed by measuring the angiotensin I generated from hog renin substrate. Angiotensin I will in turn be determined by radioimmunoassay. The nature of each compound's inhibitory activity and its inhibitory constant (Ki) will be determined through the use of Dixon plots. The specificity of the compounds will be determined by comparing their ability to inhibit renin with their ability to inhibit the related aspartyl proteases pepsin and cathepsin D. Pepsin and cathepsin D activity will be assayed by measuring spectrophotometrically the products of hemoglobin proteolysis. The results obtained from these inhibition studies will be used to determine the structural and stereochemical features which are required for maximum renin inhibitory activity.